THE CELL BIOLOGY OF THE PANCREATIC BETA CELL NIH GUIDE, Volume 26, Number 34, October 10, 1997 RFA: DK-98-003 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated research grant applications to elucidate the pathways and factors responsible for the development and maintenance of beta cells in the pancreas. Current evidence suggests that the endocrine pancreas is derived from progenitor cells in the ducts of the exocrine portion of the pancreas. An expanded knowledge of the precise location and nature of these putative progenitor cells, the factor(s) responsible for differentiation into endocrine cells, the lineage dependent factors responsible for development of alpha, beta and delta cells, the trans-acting factors which subsequently regulate expression of the genes for the hormones themselves, and the local growth factors which comprise the milieu of the endocrine islet is crucial to the development of strategies for islet and/or B cell regeneration. This solicitation is intended to stimulate the application of advances in cell biology and molecular biology to the study of the cell biology of the pancreatic beta cell. Collaborative efforts that link expertise in cell biology to expertise in diabetes are strongly encouraged. Also, two-year pilot and feasibility applications are available within this solicitation. It is anticipated that results obtained by studies supported by this solicitation will aid in the development of improved therapies for the treatment of diabetes mellitus. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, The Cell Biology of Pancreatic Beta Cells, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit organizations, public or private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the NIH research project grant (R01) award, the FIRST (R29) award, or the exploratory/developmental award (R21). The R21 awards are to demonstrate feasibility and to obtain preliminary data under circumstances of strong rational. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under Public Health Service (PHS) grants policy as stated in the PHS Grants Policy Statement. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The total requested project period for an application submitted in response to this RFA may not exceed five years. A maximum of three years can be requested for foreign awards. Applicants for the R01 mechanism are encouraged to limit their request to $160,000 in direct costs for the initial budget period unless there is appropriate justification for an expanded scope that must not exceed a first year limit of $250,000 direct costs. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to 2 years. Applicants for the R29 are limited to the National Institute of Health's guidelines for this award. Budget escalations in future years should be limited to 3% of non-recurring costs. The anticipated award date is September 30, 1998. FUNDS AVAILABLE For FY 1998, $4 million will be committed to fund applications submitted in response to this RFA. It is anticipated that 12 to 16 awards will be made. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Diabetes Mellitus affects approximately 16 million people in the United States. Individuals with Type 1 diabetes mellitus have lost their ability to produce insulin due to the immune destruction of their pancreatic beta cells, which secrete insulin. Individuals with Type 2 diabetes mellitus have lost their ability to over-produce insulin to maintain euglycemia in the presence of insulin resistance. Thus, both major forms of diabetes mellitus demonstrate a loss of sufficient insulin production by the beta cell. The results of the Diabetes Control and Complications Trial indicate that maintenance of near normal glycemic levels can reduce and delay the onset of the devastating complications of diabetes. Therefore, establishing methods of achieving and maintaining euglycemia will have enormous implications for the health and quality of life of individuals with diabetes. To this end, researchers have tried to develop cellular approaches to insulin replacement. These have included replacement of beta cells (islet transplantation) or utilization of another cell to produce insulin in response to glucose (bioengineered beta cells). To date these efforts have yielded limited success in large part due to our lack of knowledge of the origins, development and regenerative capacity of beta cells. The present solicitation seeks to foster research in these areas that can be applied to improved therapies in the future. SCOPE AND OBJECTIVES It is thought that the endocrine pancreas is derived from stem cells in the ducts of the exocrine portion of the pancreas. However, there is a paucity of information on the inductive signals that control the development of the pancreas and the generation of the individual differentiated cell types. Progress has been made on the identification of transcription factors involved in pancreatic development and understanding the potential role of certain transcription factors in the impaired insulin production and reduced beta-cell mass manifested in Type 2 diabetes mellitus. Spatial identity and patterning in the differentiation of tissues during embryonic development is regulated by the interplay between homeobox (Hox) genes and other hormones, local growth factors, and cytokines. Patterning in complex endocrine organs, such as the anterior pituitary involves key developmentally expressed signaling genes including the POU domain proteins. More recently, evidence has accumulated to suggest that development of the well-differentiated cells of the endocrine pancreas also involve developmentally expressed genes. For example, ISL1, a LIM-homeodomain protein capable of interaction with an insulin gene cis-element, appears to be required in pancreatic endodermal cells for the generation of endocrine cells, and IDX-1, or PDX-1, appears to be responsible for the initial differentiation of precursor cells in the primitive pancreas into endocrine cells. Further expression of other cis- and trans-acting factors appears to subsequently regulate the expression of genes, which express somatostatin in delta cells, glucagon in alpha cells, and insulin in beta cells. Indeed, a human mutation in such a gene results in pancreatic agenesis. The scope of the present solicitation includes the acquisition of knowledge of the precise location, nature, and markers for these putative stem cells, the factor(s) responsible for differentiation into endocrine cells, the lineage dependent factors responsible for development of alpha, beta, and delta cells, the trans-acting factors which subsequently regulate expression of the genes for the hormones, themselves, the local growth factors which comprise the milieu of the endocrine islet, and growth factors for the propagation of beta cells or their precursors in vitro. This knowledge is crucial to the development of strategies for islet and/or beta cell regeneration. Such new understanding would also foster longer-term approaches to gene therapy for diabetes. Relevant topics listed below are examples and should not be construed as required or limiting. o Determine the location and identity of the stem cells, which differentiate into cells of the endocrine pancreas o Establish cellular markers for isolating lineages of pancreatic stem cells o Identify the factor or factors which provide the signal for the earliest differentiation of pancreatic endocrine cells and which subsequently regulate patterning in the endocrine pancreas o Identify the factors and/or systemic hormones/local growth factors, which regulate the growth and development of the cellular subpopulations of the endocrine pancreas o Determine the trans-acting factors that determine the mature cell phenotype in the separate cell populations of the endocrine pancreas, including regulation of hormone expression o Develop approaches that can be used to identify and regenerate specific populations of cells within the pancreatic islets o Identify the sources and nature of the inductive signals that control pancreas morphogenesis and cytodifferentiation o Study the mechanisms involved in beta cell growth during pregnancy o Examine the possibility of beta cell neogenesis in pathological states in man, e.g. chronic pancreatitis, obesity, type 1 and type 2 diabetes mellitus o Identify syndromes affecting the endocrine pancreas in order to identify the involved genes o Identify key events and molecules in the switch between beta cell clonal expansion and terminal differentiation o Identify factors that maintain terminal differentiation o Explain the mechanism of "glucose toxicity" in the beta cell and/or develop approaches to prevent it o Clarify the molecular mechanisms involved in apoptosis of the beta cell and the means of intervening in this process o Elucidate the role of cell-cell interactions within the islet to explain the differences between isolated beta cells and islets o Ascertain the involvement of paracrine factors and/or adhesion molecules in beta cell growth and differentiation INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by February 19, 1998, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health 6701 Rockledge Drive, MSC-7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: asknih@od.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, plus three signed photocopies, in one package to: Center for Scientific Review (formerly DRG) NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F - MSC 6600 Bethesda, MD 20892-6600 FIRST (R29) award applications must include at least three sealed letter of reference attached to the face page of the original application. FIRST (R29) award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applications must be received by March 19, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? o Appropriateness of the proposed budget and duration in relation to the proposed research. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA The anticipated date of award is September 30, 1998. The factors that will be used to make award decisions include: o scientific and technical merit as determined by peer review, o availability of funds, and o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joan T. Harmon, Ph.D. Chief, Diabetes Research Section, DPB, DDEMD National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 5AN-18G - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8808 FAX: (301) 480-3503 Email: Joan_Harmon@NIH.GOV Direct inquiries regarding fiscal and administrative matters to: Nancy C. Dixon Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 Email: dixonn@extra.niddk.nih.gov Schedule Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 Initial Review: June/July 1998 Second Level Review: September 1998 Anticipated Date of Award: September 30, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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